Project 3 Abstract Despite recent progress in establishing clinical criteria for ME/CFS, diagnosis is delayed in many patients, largely due to an absence of objective clinical and laboratory tests for disease. An additional challenge for patients and clinicians alike is that the onset and course of ME/CFS are variable, as are comorbidities. The implications of variability are myriad and include potential for differences in pathways to illness, prognosis, and management. This project will lay the foundation for resolving diagnostic and prognostic uncertainty, distinguishing sub-types, enabling insights into pathogenesis, and facilitating management of illness through pursuit of three specific aims. In Aim 1, we will establish a hub for state-of-the-art translational research based on the CfS for ME/CFS clinical network. The network will be fully committed to the NINDS Common Data Elements project and to collection of survey data and biological samples needed for rigorous clinical research. We will also design a mobile app, myME/CFS, to help patients and physicians acquire valuable longitudinal data and personally and clinically manage the illness. In Aim 2, we will mine existing databases to identify clinical sub-types that differ in presentation, course, comorbidities, family medical history, or other features. In Aim 3, we will assess the clinical utility of a simple office-based test for autonomic dysfunction, the Lean Test. We will also assess the impact of the Lean Test and an Exercise Tolerance Test on plasma metabolomics and PBMC transcriptomics, thereby integrating this clinical research project with the two basic science projects in the CfS for ME/CFS.